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Guideline strongly recommends hydroxyurea, transfusion therapy for sickle cell disease
An expert panel convened by the NHLBI strongly recommends hydroxyurea and transfusion therapy for most patients with sickle cell disease, according to a summary of the evidence-based guidelines published in JAMA.
“Two important disease-altering therapies exist for the treatment of people with sickle cell disease — hydroxyurea and chronic transfusions — both of which are under-utilized, leaving patients to suffer when some of the complications could have been prevented,” Barbara P. Yawn, MD, MSc, MSPH, director of research at the Olmsted Medical Center in Rochester, Minn., told HemOnc Today. “These guidelines were developed to increase awareness and the ability of additional physicians and their staffs to provide these therapies.”
Yawn and colleagues strongly recommended hydroxyurea therapy for adults with sickle cell anemia who had at least three moderate to severe pain crises associated with sickle cell disease (SCD) in 1 year. The panel also recommended hydroxyurea for adults with sickle cell anemia whose quality of life is affected by disease-related pain, severe or recurrent acute chest syndrome, or severe symptomatic chronic anemia.
Barbara P. Yawn
Hydroxyurea therapy is strongly recommended for infants and children aged 9 months to 42 months, and moderately recommended for those aged older than 42 months — regardless of clinical severity — in order to reduce disease complications.
The guidelines recommend transfusion therapy for adults and children with sickle cell anemia before a surgical procedure in order to elevate their hemoglobin level to 10 g/dL.
“The primary care physician who cares for at-risk patients must either learn how to provide the disease-modifying therapies or collaborate with a consultant or center who can to assure that all eligible patients are educated about and offered these therapies when appropriate,” Yawn said.
Maintenance recommendations
The guidelines also contain strong recommendations for health maintenance, as well as for managing acute and chronic complications.
All children with the HbSS genotype should receive oral penicillin prophylaxis twice daily until age 5 years, and all patients with SCD should receive the Streptococcus pneumoniae vaccine, according to the recommendations.
Children with sickle cell anemia also should be screened annually with transcranial Doppler from age 2 years to 16 years due to the risk for stroke.
“Several important preventive measures are recommended for everyone with SCD, such as immunization for pneumococcal disease and daily prophylactic penicillin beginning in infancy and transcranial Doppler screening beginning in early childhood,” Yawn said. “Every patient needs to receive these preventive measures.”
Among the strong recommendations for managing acute complications is the guidance that all patients should receive opioids for severe pain from vaso-occlusive crisis, and that patients with vaso-occlusive crisis should use incentive spirometry during hospitalization.
“For individuals with SCD presenting with an acute pain crisis or vaso-occlusive crisis, remember they may have no physical findings except those associated with acute pain,” Yawn said. “They need to be treated immediately with sufficient opioids to decrease the pain, and then evaluated for complications and possible etiologies. In children with SCD who present with a fever, evaluation to rule out serious infections is necessary.”
The guidelines also outline recommendations for managing acute chest syndrome, acute stroke, priapism, hepatobiliary complications, splenic sequestration and acute renal failure, and for chronic complications such as avascular necrosis, pulmonary hypertension and ophthalmologic complications.
Need for better evidence
Despite the range of strong recommendations in the guidelines, many recommendations are based on low- to moderate-quality evidence, Yawn and colleagues wrote. Only seven of the strong recommendations were supported by high-quality evidence, they said.
A lack of randomized controlled clinical trials highlights many knowledge gaps and deficiencies in caring for patients with SCD, researchers said.
“The need for research is vast in studying SCD and ranges from simple epidemiology studies to follow large groups of patients to better understand the course of SCD and its complications, to studies that assess the impact and value of screening, early intervention and treatment of many complications of SCD, including evaluation for problems such as kidney disease, stroke and cognitive impairment prevention,” Yawn said.
Due to the curative nature of the hematopoietic stem cell transplantation (HSCT), the guidelines should have contained more information about the procedure, Michael R. DeBaun, MD, MPH, director of the Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease of the Vanderbilt University School of Medicine in Nashville, Tenn., wrote in an accompanying editorial.
“Given the chronic nature of this disease, and recent scientific advantages, an increasing number of parents and adults will seek a definitive cure for SCD,” DeBaun wrote. “The medical community, in conjunction with patients, will need guidance to deal with the complex question of when to consider HSCT in the near future.”
Yawn agreed that HSCT is an area in need of more study.
“A major priority will be to follow up on the work related to HSCT,” Yawn said. “It holds the promise of a cure but has received limited study. Who is eligible, what are the complications, what percent of recipients will be cured and how do we make this accessible to all eligible individuals?”
References:
Yawn BP. JAMA. 2014;doi:10.1001/jama.2014.10517.
For more information:
Barbara P. Yawn, MD, MSc, MSPH, can be reached at Olmsted Medical Center, Department of Research and Education, 210 Ninth St. SE, Rochester, MN 55904; email: byawn@olmmed.org.
Disclosure: Yawn and DeBaun report no relevant financial disclosures. See the study for a list of the other researchers’ relevant financial disclosures.
Perspective
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Yawn and colleagues review, grade and synthesize the available literature, providing useful guidelines that summarize the long-awaited companion report from the NIH. High-quality data are presented clearly, but they are intermingled with numerous recommendations based on consensus or low-quality data. Although frustrating, the latter cannot be avoided as research and data are lacking, and some form of reference guidelines are desperately needed to standardize quality care.
Although expansive in scope, there are some obvious absences, such as guidance regarding pulmonary hypertension screening, and the exciting opportunity for cure with stem cell transplantation. In contrast, the clear theme of pushing for the expanded use of hydroxyurea and providing guidelines for its management is of vast importance.
Overall, these guidelines are commendable and dearly needed. Any deficits in this work reinforce the dire need for more funding of sickle cell research, and the need to recruit more trainees and investigators into the field.
Perspective
Back to TopIn the United States, routine neonatal screening and access to improved management and treatment strategies have reduced morbidity and significantly improved life expectancy. However, numerous barriers to optimal care — especially during adulthood — contribute to suboptimal outcomes for many. Barriers include inadequate knowledge, expertise and communication among primary and specialty care providers; lack of important disease-specific services in many communities; inadequate insurance coverage for services that are available; and patient mistrust of providers and health care systems.
In this context, the release of the long-awaited Evidence-Based Management of Sickle Cell Disease: Expert Panel Report 2014 is an important milestone. Because these new recommendations are rigorously and transparently evidence-based, they should have significant credibility with providers, patients and families, health care administrators and payers. If widely disseminated and implemented, these new guidelines should improve the quality of care. The report also may prove to be an effective advocacy tool for providers, patients and community-based organizations who want to expand the availability of — and third-party payer coverage for — important services.
It also is important to appreciate the limitations of these guidelines, many of which were highlighted in the executive summary and an accompanying editorial by Michael R. DeBaun, MD, MPH, published in JAMA. Because relatively few phase 3 therapeutic trials have been performed in SCD, some important aspects of care are addressed by recommendations based on relatively weak evidence; others are not addressed at all. Most therapeutic trials have been designed to address relatively short-term endpoints (eg, rates of acute illness events, use for blood transfusion over a 2- to 3-year period), but outcomes most important to patients and families are often longer term. For example, hydroxyurea is recommended for children with sickle cell anemia ≥9 months of age to reduce acute complications of SCD, but many families and some providers are as much or more concerned about outcomes 10 to 20 years or more in the future. Thus, it will be important to find public and private funding to support longer-duration trials and population-based registries to help determine, for example, whether starting hydroxyurea treatment at age 1 to 2 years will be associated with less chronic organ damage and better long-term outcomes than waiting to start treatment at older ages when the burden of disease is greater. Similarly, we need to be able to compare both short- and long-term outcomes of hydroxyurea therapy with those of stem cell transplantation in carefully matched groups of patients.
Hematologists now have an obligation to review this new document and consider how it might improve the care they provide and support local quality improvement activities. In so doing, they need to carefully differentiate among strong, moderate and weak recommendations. The expert panel intended that strong and moderate-strength recommendations be used to populate protocols of care, but that weak or moderate-strength recommendations not be used to generate quality-of-care indicators or accountability measures or to affect insurance reimbursement. It is important for both providers and payers to note that some recommendations not to use certain procedures (eg, pulmonary function tests, brain MRI) to screen routinely for certain complications apply only to “asymptomatic individuals,” which clearly places an onus on providers to carefully inquire about, document and investigate symptoms such as chronic cough, poor exercise tolerance, declining academic achievement, etc.
Lastly, it would be unfortunate if the expert panel report was used to discourage or prevent clinicians from periodically assessing the presence or absence of clinically “silent” complications, including the extent to which chronic damage to the brain and others organs is present. For many patients and families, documentation of chronic organ damage may influence perceptions of disease severity and acceptance of — and adherence with — hydroxyurea or other treatments.